Construction Of Medium-ring Heterocyclic Drug Molecular Skeletons Via Transition Metal-catalyzed Site-selective C-H Functionalization

BackgroundMedium-ring heterocyclic compounds are widely found in natural products,drug molecules and other molecules with physiological and pharmacological activities.Nevertheless,during the development of medicinal chemistry,traditional synthetic methods have disadvantages such as cumbersome steps and large resource consumption.Therefore,it is imminent for developing new reaction modes to construct heterocyclic skeletons efficiently.With an increasingly development of metal chemistry,transition-metal（TM）-catalyzed direct C-H functionalization have provided for the one-pot construction of carbon-carbon or carbon-heteroatom bonds in a green and atom-economical manner.Transition-metal has bound with the substrate to form a metal intermediate which can decrease the activation energy and shorten the reaction process for efficient approaches.Having the advantages of simplifying the reaction raw materials,this protocol has developed various new reaction modes,that became one of the popular strategies in the drug synthesis and organic material field.PurposeBased on the strategy of transition-metal-catalyzed C-H activation,substrates directed by hydroxyl and amino groups were cyclized with coupling reagents such as propargyl alcohol esters and gem-difluoroalkynes to achieve chemical control and site selectivity in a diversified synthesis method,which can assemble medium-ring heterocyclic compound skeletons greenly and efficiently,and develop a variety of new reaction modes.This method not only injects new energy to enrich organic synthesis methodology,but also provides precursor compounds for complex molecular drug structures,thereby accelerating the development of new drugs.Methods（1）2-alkenylphenols and propargyl carbonates were used as substrates with Cu（OAc）₂（2 equiv）as oxidants and Cs OAc（1 equiv）as base,under the catalysis of[Cp*Rh Cl₂]₂,the reaction was carried out in DMF at 120 ^oC for 24 h.We have carried out control experiments,kinetic isotope experiments and DFT calculations to clarify the reaction mechanism.（2）Using[Cp*Rh（III）]with a Cp ligand equipped electron-donating group as catalyst,N-tosyl-2-（prop-1-en-2-yl）aniline was chosen as model substrate and the reaction was stirred in DCE at 80 ^oC for 24 h under the action of KOPiv（1 equiv）.We have explored the reaction process through DFT calculation and control experiments.（3）By using the 1-naphthol as substrate,the reaction was carried out with Cs OAc（1 equiv）as base and coupling with gem-difluoromethylene alkynes in dioxane at 80 ^oC for 24 h under rhodium（III）-catalyzed reaction conditions.We have carried out control experiments and deuteration experiments to propose catalytic cycle of the reaction.Results（1）Using two O-containing functional groups as transient assisting groups（AGs）,a mild reaction mode with Rh（III）-catalyzed[5+2]annulation of easily available2-alkenylphenols with propargyl carbonates was developed.With broad substrate range and good functional group tolerance,seven-membered ring benzoxepin derivatives were constructed,which was further confirmed by X-ray diffraction analysis.We also proposed the reasonable reaction mechanism by combing density functional theory（DFT）calculations and the experimental investigations.（2）In a powerful catalytic system combined with Cp*^CyRh（III）catalyst and a KOPiv additive,the first intramolecular dehydrogenative cross-coupling using N-arylsulfonyl（or aroyl）-2-alkenylanilides as the viable substrates via site-selective aryl C-H activation was reported,which provided eight-membered sultams/lactams structure skeleton.Experimental and computational studies revealed that such a transformation involves aryl C-H activation/alkene insertion/β-H elimination/hydrogen-transfer process and the Rh（III）-H species as the active intermediate with the concomitant release of H₂ as the major byproduct,thus enabling redox-neutral and highly atom-economical features.（3）The Rh（III）-catalyzed C-H couplings of 1-naphthols with gem-difluoromethylene alkynes have been realized for the direct construction of difluorinated dihydrobenzo[de]chromenes with broad substrate/functional group compatibility and good regio-/chemoselectivity.The unique fluorine effects account for the unconventional reaction path involving intramolecular 1,3-H migration process to afford an exocyclic double bond.ConclusionsIn summary,based on the strategy of TM-catalyzed direct C-H functionalization,we have developed an efficient rhodium（III）-catalyzed cascade to furnish a series of medium-ring heterocyclic skeletons like benzoxepine,eight-membered sultams/lactams and difluorinated dihydrobenzo[de]chromene derivatives by employing hydroxyl and amino as directing groups.In addition,combined experimental and computational studies,we explored the reaction mechanism and inferred a reasonable circulation path.Therefore,this study provided more new ideas for the synthesis of medium-ring heterocyclic molecular skeletons in an efficient and mild manner.